1. Field of the Invention
The present invention is directed to methods of treating neoplastic diseases. More particularly, methods for using compounds which have a cross-conjugated cyclopentenone moiety, and which lack an .alpha.,.beta.-unsaturated .gamma.-lactone moiety are provided.
2. Description of the Prior Art
Cellular homeostasis is a delicate balance between cell production and cell removal. Homeostasis depends to a large extent on two alternative modes of existence of animal cells: the quiescent and the proliferative. The growth and division of normal cells is usually regulated by the action of various endogenous stimulators and inhibitors. When this delicate balance is perturbed, hyperproliferation or neoplasia may develop.
Neoplastic disorders constitute a major health problem in the world today. Few antineoplastic agents have the dual beneficial properties of both efficacy and reduced toxicity. The vast majority of antineoplastic agents currently in use are generally both relatively non-tumor specific, as well as toxic to the individual being treated. For example, typical toxicities associated with antitumor therapeutic agents include immune suppression, bone marrow depression, alopecia, and a host of other unwanted side effects. The key in identifying beneficial antineoplastic agents is in isolating agents which are capable of inhibiting neoplastic growth without adversely affecting normal cell growth.
An excellent source of agents having the potential for treating neoplastic conditions is plants such as herbs. There is substantial history of the use of herbal medicines for treating a variety of diseases. Although certain claims of these herbal medicaments can be discounted, others necessitate closer scrutiny. Isolation and identification of compounds from plants and herbs provides clues to beneficial pharmaceutical agents.
Turkish herbal medicines are somewhat unique in this regard. Since Istanbul was an intersection of major trade routes in older civilizations, Turkish traditional medicines readily incorporated the knowledge and herbal applications of the highly advanced Chinese, Aryuvedic (Indian), Persian and other Islamic medicines into their own system. In the Ottoman Empire, the traditional medical system reached a highly developed state, well beyond that initiated by foreign influence, due to the presence of a large number of plant species endemic to the area now known as Turkey.
One such "medicine" which had been used through the centuries to treat "conditions" of internal blockages was called "hindiba" in Turkish. Three different primary herbal species, Cichorium endivia (cultivated endive), Lactuca scariola (cultivated scariola or Italian endive), and wild chicory (C. intybus) were all used to prepare hindiba, along with numerous other local substitute species (such as Taraxacum species and others). The ancient Turkish, Islamic and other medicinal texts suggest that hindiba prepared from wild chicory was the most important historical agent in treating internal blockages. The Ottoman texts also cautioned that hindiba was somewhat unstable to aging and to heat.
For years investigators used cytotoxicity against tumor cells as a criterion for assessing antitumor activity. Compounds which were not cytotoxic in those assays were not considered useful in tumor suppression or control.
The prior art reveals that compounds (some of which are of herbal origin) having a O.dbd.C--C.dbd.CH.sub.2 moiety as part of an ester, ketone, or lactone, and more particularly as an .alpha.,.beta.-unsaturated .gamma.-lactone moiety, may have such "antineoplastic" or "antitumor" properties. However, these properties are related to the cytotoxic properties of the compounds, and not selective antineoplastic properties. Most of these compounds were tested using the classic cell lines L1210 or P388 lymphoma cells, which readily respond to cytotoxic agents. A number of these compounds are sesquiterpene lactones having an .alpha.,.beta.-unsaturated .gamma.-lactone group. It is generally recognized that these compounds of the prior art, which were identified as having "anticancer" properties, were exhibiting nonselective cytotoxic properties associated with the .alpha.,.beta.-unsaturated .gamma.-lactone moieties. The compounds were toxic to all cells and had little or no therapeutic window. The cytotoxic properties associated with compounds containing an .alpha.,.beta.-unsaturated .gamma.-lactone moiety limit their therapeutic effectiveness since they affect normal cells as well as neoplastic cells.
Since Cichorium intybus and C. endivia were known medicinally, these species were also scrutinized for biologically significant natural products, with particular interest paid to the sesquiterpene lactones bearing the .alpha.,.beta.-unsaturated .gamma.-lactone moiety, since the prior art was such as to equate cytotoxic with antineoplastic activity. Indeed, the well-known sesquiterpene lactones such as lactucin, lactupicrin, 8-deoxylactucin, and 15-O-.beta.-D-glucopyranosyl-8-deoxylactucin, all of which bear the .alpha.,.beta.-unsaturated .gamma.-lactone moiety, were found in these Cichorium species and were examined for cytotoxic activity. See Schenck, G., Graf, H. Arch. Pharm. (Weinheim) 1936, 274, 537; Leclercq, E. J. Chromatogr. 1984, 283, 441; Pyrek, J. St. Phytochemistry 1985, 24, 186; Seto, M., Miyase, T., Umehara, K., Ueno, A., Hirano, Y., Otani, N. Chem. Pharm. Bull. 1989, 36, 2423. 11.beta.,13-Dihydrolactucin and its 15-O-.beta.-D-glucopyranoside were also found in C. intybus, but since these compounds did not bear the .alpha.,.beta.-unsaturated .gamma.-lactone moiety, they either were not tested for cytotoxic activity, or were tested but were found to be non-cytotoxic since no activity was reported.
Lee and coworkers suggested in 1977 that the cyclopentenone unit, commonly found in pseudoguaianolides such as helenalin, plenolin, and tenulin, is responsible for in vitro cytotoxic activity against cancer cell lines; Lee, K.-H., Hall, I. H., Mar, E.-C., Starnes, C. O., ElGebaly, S. A., Waddell, T. G., Hadgraft, R. I., Ruffner, C. G., Weidner, I. Science 1977, 196, 533. These workers, however, were still equating nonselective cytotoxicity with antitmnor activity, and more importantly, the compounds they considered did not possess the cross-conjugated cyclopentenone structure which is crucial for the activity we have observed. In summary, the prior art led away from the compounds of this invention by focusing on cytotoxicity. Compounds which did not exhibit cytotoxicity were not deemed to be of interest as antineoplastic agents.